Heterozygous Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene Are Associated With Primary Osteoporosis in Children

Abstract

Three of 20 patients with juvenile osteoporosis were found to have a heterozygous mutation in the LRP5 gene. No mutations were found in the type I collagen genes. Mutations in the other family members with similar bone phenotype confirmed that LRP5 has a role in both juvenile and adult osteoporosis. Introduction:The gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5) gene has recently been shown to affect bone mass accrual during growth and to be involved in osteoporosispseudoglioma syndrome and a high bone mass phenotype. Mutations in the type I collagen genes (COL1A1 and COL1A2) are known to cause osteogenesis imperfecta, characterized by increased bone fragility. Materials and Methods: Here we analyzed COL1A1, COL1A2, and LRP5 for mutations in 20 pediatric patients with primary osteoporosis characterized by low BMD, recurrent fractures, and absent extraskeletal manifestations. Results and Conclusions:No mutations were detected in the type I collagen genes, but two missense mutations (A29T and R1036Q) and one frameshift mutation (C913fs) were found in the LRP5 gene in three of the patients. The frameshift mutation was also seen in the proband's father and brother, who both were found to have significant osteoporosis. R1036Q was observed in the proband's mother and two brothers, who all had osteoporosis. These results indicate that heterozygous mutations in the LRP5 gene can cause osteoporosis in both children and adults.

Bone Material Properties in Osteogenesis Imperfecta

“…No Homozygous -osteoporosis pseudoglioma syndrome; (123) Heterozygous -osteoporosis and/or vitreoretinopathy (124) …”

PLS3 Mutations in X-Linked Osteoporosis with Fractures

“…The investigation of rare mendelian disorders with decreased BMD as a key diagnostic feature constitutes a strategy for identifying genetic determinants of osteoporosis. [3][4][5][6][7] We identified families with X-linked osteoporosis and fractures among patients with negative tests for the genes encoding collagen type Iα1 and type Iα2 (COL1A1 and COL1A2, respectively) who had been referred to us for diagnosis or ruling out of osteogenesis imperfecta type I. Osteoporosis with fractures as an X-linked trait has been reported by Sillence. 8 We now report data from five families with X-linked osteoporosis and fractures related to pathogenic variants in the gene for plastin 3 (PLS3), provide functional evidence that PLS3 is a bone-regulatory protein, and describe a rare variant or single-nucleotide polymorphism (SNP) associated with decreased BMD and an increased risk of fracture among heterozygous women in the general population.…”

Genetic predisposition for femoral neck stress fractures in military conscripts

“…The function of LRP5 in bone development, however, is indisputable [41]; mutations in LRP5 cause various bone disorders [20,42] and polymorphisms are associated with BMD and bone mineral content in general [43], but also with reduced BMD and fractures [44]. Mouse studies demonstrated that mutations in Lrp5 affect bone formation sensitivity in response to normal mechanical loading [45,46], and thus the LRP5 haplotype A-G-G-C might affect bone sensitivity and response to mechanical loading.…”